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New and Emerging Approaches to Ocular Surface Inflammation

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New and Emerging Approaches to Ocular Surface Inflammation MEDICAL ED NG UC UI AT A CONTINUING TIN IO CON N MEDICAL EDUCATION PUBLICATION CME ISSUE 20 New and Emerging Approaches to Ocular Surface In ammation A STEPHEN PFLUGFELDER, MD The immune zyme, and immunoglobu- environment of the ocular surface o ers multiple lins, which exert antimicro- opportunities for pharmaceutical intervention. bial and antiinflammatory Following the exa mple of other medical specialties, eff ects.1 Transmembrane and ophthalmologists are likely to see an in ux of more secreted mucins are released targeted therapies for ocular surface in ammation. in response to foreign, nox- ious, or antigenic stimuli. B Secreted mucins (such as Under normal circumstances, complex, tightly woven MUC5AC and MUC7) may immune mechanisms on the ocular surface keep the eye safe participate in defense by from invasion or insult. A certain level of transient, physi- preventing pathogen bind- ological infl ammation is a necessary part of this operation, ing or by surrounding and dominated by the elements of the innate or intrinsic immune removing contaminants.2 FIGURE 1 A. Neovascularization and system. Infl ammation becomes pathological when these same Resident immune cells like infi ltrates in a 13-year-old patient elements become dysregulated, as in autoimmune or chronic macrophages deal with ocu- with chronic recurrent blepharitis infl ammatory conditions, and go from being protective to and marginal keratitis. B. Regression lar surface invasion in rela- of corneal neovascularization after 1 damaging of host ocular surface tissues. tively nonspecifi c ways, but month of topical corticosteroid. (Images Treating pathological infl ammation always carries the risk do have pattern-recognition courtesy of Dr. Pfl ugfelder.) of interrupting or disabling important physiological immune receptors (including toll- and protections, an understanding that continues to drive antiin- NOD-like receptors) that can respond to molecular patterns fl ammatory and immunomodulatory drug development ef- associated with pathogens or tissue damage.3 forts toward more specifi c targets. Key to success will be under- Once activated, pattern recognition receptors trigger signal- standing the pathways and infl ammatory mediators at play in ing pathways that lead to the production of proinfl ammatory conditions—particularly dry eye disease (DED), allergy, and, cytokines, chemokines, and proteins associated with antimi- oft en, infection—characterized by pathological infl ammation. crobial and tissue repair actions. Key mediators include tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 and IL-6.1,3 In INTERSECTING IMMUNE PATHWAYS In addition to the physical barriers created by the mucin See INSIDE for: glycocalyx and the tight junctions between ocular surface Infl ammation Management and Prevention of epithelial cells, innate ocular surface immune mechanisms Corneal Graft Rejection by Pedram Hamrah, MD, FACS include secretory proteins in tears, such as lactoferrin, lyso- To obtain CME credit for this activity, go to http://cme.ufl .edu/ed/self-study/toai/ Supported byTopics an unrestricted in OCULAR educational ANTIINFLAMMATORIES grant from Shire. 1 addition to immune cells, resident ocular TOPICS IN OCULAR ANTIINFLAMMATORIES, ISSUE 20 surface epithelial cells participate in some STATEMENT OF NEED (JavaScript™ and Java™ enabled). For Mac® users: Mac OS® of these mechanisms and have their own The control of ocular infl ammation is a critical aspect of X 10.4 (Tiger®) or newer; Safari™ 3.0 or newer; Mozilla® pattern recognition receptors, including medical and surgical ophthalmic practice. Despite their Firefox® 2.0 or newer (JavaScript™ and Java™ enabled). Internet connection required: Cable modem, DSL, or 4,5 side eff ects, antiinfl ammatory drugs are used to treat a toll-like receptors (TLR) 3 and TLR4. very wide range of conditions throughout the eye, from better. When activated, these receptors help ocular surface disease and allergic conjunctivitis to poste- rior segment conditions. Use of antiinfl ammatory agents DATE OF ORIGINAL RELEASE January 2018. Approved ramp up the immune response by releas- is also critical in ocular surgery, contributing greatly to for a period of 12 months. patient comfort and positive outcomes. ing more proinfl ammatory mediators. ACCREDITATION STATEMENT The ocular antiinfl ammatory landscape is changing as This activity has been planned and implemented in ac- Whether the inciting event is micro- research reveals more about the role of infl ammation in cordance with the accreditation requirements and poli- a range of ocular conditions and as new antiinfl ammatory bial invasion, allergen exposure, or hy- cies of the Accreditation Council for Continuing Medical agents enter the market.1,2 Twenty years ago, for example, Education (ACCME) through the joint providership of the perosmolar stress, eventually this cascade the idea of using a topical corticosteroid to treat dry eye University of Florida College of Medicine and Candeo and/or allergic conjunctivitis was viewed with alarm; of infl ammatory signaling can set the Clinical/Science Communications, LLC. The University of today, it is accepted practice. stage for adaptive immune mechanisms. Florida College of Medicine is accredited by the ACCME Although corticosteroids and nonsteroidal antiinfl am- to provide continuing medical education for physicians. Adaptive immune responses are matory drugs (NSAIDs) have been the mainstays of the ocular anti-infl ammatory armamentarium, a number of initiated when antigen presenting cells CREDIT DESIGNATION STATEMENT new agents with novel mechanisms of action (and new The University of Florida College of Medicine designates ocular drug delivery systems) have come to market or are this enduring material for a maximum of 1 AMA PRA (APCs), primarily dendritic cells on 3,4 being made ready for market. Cate gory 1 Credit™. Physicians should claim only the the ocular surface, encounter a specifi c As indications expand and change, and as new drugs, credit commensurate with the extent of their participa- antigen. APCs activate eff ector T cells or formulations, and delivery systems become available, tion in the activity. clinicians require up-to-date protocols for drug selec- prime naive T cells in the regional lymph tion and use. Such protocols are also needed for routine EDITORIAL BOARD / FACULTY ADVISORS nodes. Th e T cells then migrate back to (but nevertheless off -label) uses of corticosteroids and Marguerite B. McDonald, MD, FACS, practices at NSAIDs because important diff erences in effi cacy, safety, Ophthalmic Consultants of Long Island, and is a clinical the target tissue, disable and remove in- and tolerability exist between these classes and among professor of ophthalmology at the New York University vading pathogens, and release cytokines formulations within each of these classes.5,6 School of Medicine. She is also an adjunct clinical profes- By putting the latest published evidence into the context sor of ophthalmology at Tulane University Health Sciences that can trigger further cell recruitment of current clinical practice, Topics in Ocular Antiinfl amma- Center. She is a consultant to Allergan, Alcon, Abbott and cause tissue damage.6 tories equips ophthalmologists to maintain competen- Medical Optics, Bausch + Lomb, FOCUS Laboratories, cies and narrow gaps between their actual and optimal Shire, OCuSOFT, Altaire, Bio-Tissue, BlephEx, Oculus USA, In the case of noninfectious infl am- infl ammation management practices, across the range and Optical Express. mation, numerous possible autoantigens of clinical situations in which current and novel ocular Victor L. Perez, MD, is a professor of ophthalmology at antiinfl ammatories may be used. the Duke University School of Medicine. He is also the have been identifi ed as triggers of chron- director of Duke Eye Center's Ocular Immunology Cen- ic adaptive ocular surface responses.7 REFERENCES ter and Ocular Surface Program. He has received grant/ 1. Song JS, Hyon JY, Lee D, et al. Current practice pattern research support from the National Institutes of Health, Various subsets of T helper (Th) for dry eye patients in South Korea: a multicenter study. and is a consultant for Allergan, EyeGate, and Shire. He is cells may be generated depending on Korean Journal of Ophthalmology. 2014;28(2):115-21. also a stock shareholder for EyeGate. 2. Ciulla TA, Harris A, McIntyre N, Jonescu-Cuypers C. Treat- Matthew J. Gray, MD, is an assistant professor in the patterns encountered during antigen ment of diabetic macular edema with sustained-release department of ophthalmology at the University of presentation. Th1 and Th17 cells are glucocorticoids: intravitreal triamcinolone acetonide, Florida College of Medicine. He states that in the past 12 dexamethasone implant, and fl uocinolone acetonide months, he has not had a fi nancial relationship with any proinfl ammatory and implicated in the implant. Expert Opin Pharmacother. 2014;15(7):953-9. commercial organization that produces, markets, resells, pathogenesis DED; they secrete inter- 3. Maya JR, Sadiq MA, Zapata LJ, et al. Emerging therapies or distributes healthcare goods or services consumed by feron (IFN)-gamma and IL-17, respec- for noninfectious uveitis: what may be coming to the or used on patients relevant to this manuscript. clinics. J Ophthalmol. 2014;2014:310329. Pedram Hamrah, MD, is associate professor of ophthal- 6,8 tively. Th 1 and Th 2 cells are involved in 4. Sheppard JD, Torkildsen GL, Lonsdale JD, et al, and mology, Tufts University
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